Malaria kills 2.1 million people per year and drug resistance to current therapies is becoming a significant problem. Plasmepsin, and aspartyl protease, is involved in the digestion of hemoglobin which is a major nutrient source for the parasite. Inhibition of hemoglobin degradation has been shown to cause parasite death. At Pharmacopeia, combinatorial libraries of small organic molecules are synthesized on beads and after each synthetic step an encoding molecule or tag is attached to the bead which allows for rapid identification of the inhibitory compounds. Our goal for this project is to identify an antimalarial clinical candidate which functions as an inhibitor of the plasmepsin enzyme. Phase I was successful in identifying potent and selective inhibitors of plasmepsin and we will continue to improve on these results during Phase II. Our goal for Phase II is to identify a bioavailable plasmepsin inhibitor through synthesis and screening of additional encoded combinatorial libraries, medicinal chemistry and pharmacokinetics. The resulting data will further our knowledge of structure-activity relationships and aid in the identification of additional selective inhibitors effective against the parasite. Additional lead optimization, pharmacokinetic, and animal efficacy studies will be required prior to identification of clinical antimalarial candidate. PROPOSED COMMERCIAL APPLICATION: Malaria kills 2.1 million people each year. Travelers to areas where malaria is endemic, such as U.S. military and government personnel, are at risk of disease and death. The development of drug resistance is making current antimalarial therapies less effective. Therefore, new antimalarial therapies are desperately needed. Combinatorial libraries and high throughput screening should expedite the discovery of more effective treatments for malaria.